Methadone is an opioid, which is widely used medically as an analgesic and an anti-addictive for use in patients with opioid dependency. Other well-known opioids used in medical treatment are hydrocodone, oxycodone and morphine. Methadone was developed by German chemists, Bockmuhl and Ehrhart, during World War II as a synthetic narcotic analgesic.
In the past, various methods have been developed to produce methadone. The method of producing methadone, also known as 6-(dimethylamino)-4,4-diphenylheptan-3-one, is disclosed in U.S. Pat. No. 4,24,274 and U.S. Pat. No. 2,601,323.
The use of methadone in medical treatment has increased over the years. However, a number of cases associated with methadone toxicities and overdose have also risen with the increase of use of methadone. Methadone confers some risk for cardiac adverse events and sudden death. Its use has been associated with arrhythmias. This effect is mediated through the ability of methadone to bind to human Etherà-go-goRelatedGene (hERG) channels in cardiacmyocytes, resulting in delayed repolarization. The risk is thought to result mainly from the use of a racemic methadone formulation that contains both (R)- and (S)-enantiomers.
The (R)-enantiomer is a mu opioid agonist responsible for therapeutic effects. The (S)-enantiomer is a poor mu agonist and can block hERG channels to a greater degree than the (R)-enantiomer, which has been postulated to be responsible for cardiac adverse events in methadone use. This information, in the context of recent studies showing a reduced effect of (R)-methadone methadone on QTc interval has generated discussion of the consideration of eliminating racemic methadone in favour of the exclusive use of (R)-methadone or buprenorphine as a means of resolving the cardiac safety issues related to current methadone treatment. A proposed solution is the use of a form of methadone that contains only the (R)-enantiomer.
Accordingly, a need still exists for a process to produce (R)-6-(dimethylamino)-4,4-diphenylheptan-3-one.